S173: T-CELL ACTIVATION AND MYELOMA CELL KILLING CONFIRM THE MODE OF ACTION OF RG6234, A NOVEL GPRC5D T-CELL ENGAGING BISPECIFIC ANTIBODY, IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA
Authors: I. Dekhtiarenko, I. Lelios, J. Attig, N. Sleiman, D. Lazzaro, I. Clausen, N. Gräfe, H.-J. Helms, E. Schindler, S. Belli, T. Fauti, J. Eckmann, P. Umana, W. Jacob, M. Schneider, C. Hasselbalch Riley, M. Hutchings, S.-S. Yoon, Y Koh, S. Manier, T. Facon, S. J. Harrison, J. Er, F. Volzone, A. Pinto, C. Montes, E. M. Ocio, A. Alfonso-Pierola, P. Rodríguez Otero, F. Offner, A. Guidetti, P. Corradini, C. Titouan, C. Hulin, C. Touzeau, P. Moreau, R. Popat, S. Leong, R. Mazza, C. Carlo-Stella, A.-M. E. Bröske
Journal: HemaSphere (2022)

Background: RG6234 is a novel T-cell engaging bispecific antibody targeting G protein-coupled receptor 5D (GPRC5D) with a unique 2:1 format. GPRC5D is highly expressed on multiple myeloma (MM) cells and concurrent binding of RG6234 to GPRC5D and CD3 on T cells results in immunological synapse formation and potent T-cell directed tumor cell killing. An ongoing Phase 1 dose-escalation study (NCT04557150) is investigating the safety, clinical activity, pharmacodynamics (PD), and pharmacokinetics of RG6234 monotherapy in patients (pts) with relapsed/refractory MM (RRMM). Clinical activity was observed during dose escalation, and the safety profile was manageable (Riley et al. EHA 2022). Aims: Here, we present preliminary clinical biomarker data highlighting PD effects after intravenous (IV) administration that confirm the mechanism of action and high potency of RG6234. Methods: Exploratory biomarker analyses included data from pts treated with RG6234 doses ranging from 0.006mg to 4.8mg in dose escalation. RG6234 was administered as an IV infusion under a step-up dosing regimen, reaching the target dose not later than 2 weeks after the priming dose. Peripheral biomarkers were evaluated using whole blood flow cytometry (n=28), plasma cytokine Protein Simple ELLA (n=33), and plasma sBCMA Protein Simple ELLA (n=26). MM cells were assessed at baseline and on-treatment by bone marrow (BM) aspirate flow cytometry and by BM biopsy CD138/CD8 immunohistochemistry. Informed consent was obtained from participating pts. The clinical cut-off date for the current analysis was January 31, 2022. Results: PD changes were observed in peripheral blood at all tested doses. Cytokines (IFNg, TNFa, CXCL10, IL6, IL10, IL2, IL8) and sCD25 peaked at 4 to 24 hours (h) following the first administration, while cytokine peak magnitudes decreased at subsequent administrations. Cytokine release was followed by transient reduction of circulating T cells at 4 h after infusion, with partial recovery of peripheral T-cell counts by Day 8 after first administration. Elevation of sCD25 and IFNg in plasma (~3.2 and 33 median fold change from baseline, respectively) together with increase in T-cell proliferation (~4 median fold increase of Ki67+CD8+ T-cells) within 72 h post first infusion indicated T-cell activation. Analysis of a limited number of paired baseline and on-treatment BM biopsies (n=13) revealed that the density of CD8+ tumor-infiltrating T cells increased upon treatment in responders, indicating T-cell recruitment towards the tumor. RG6234 induced rapid depletion of MM cells, as demonstrated by a decrease of sBCMA in the plasma of responding pts already 8 days after the first administration (median 33.5% reduction from baseline in responding pts; n=15). Moreover, at the end of Cycle 1, the majority of pts (14/15) had <1% of MM cells in BM based on flow cytometry readout. GPRC5D expression was detected at baseline in all pts with evaluable bone marrow aspirate and >20 detectable MM cells (n=16). Updated exploratory biomarker data will be presented. Summary/Conclusion: Cytokine release, T-cell activation, BM infiltration, and MM cell depletion are early PD changes seen after treatment with RG6234 and precede clinical responses. These PD changes indicate that RG6234 leads to T-cell engagement in the BM of pts with RRMM and clearly demonstrate rapid and effective T-cell mediated anti-MM activity.